Background: The relationship between metabolic syndrome (MetS) and cancer risk, and the potential mediating role of biological aging as measured by Phenotypic Age Acceleration (PhenoAgeAccel), remains insufficiently characterized.
Methods: We conducted a cross-sectional study of 12,664 participants from the National Health and Nutrition Examination Survey (NHANES, 1999-2010, 2015-2020). MetS was defined according to established criteria, cancer status was self-reported, and PhenoAgeAccel was derived from clinical biomarkers. Weighted multivariable logistic regression and formal causal mediation analysis were employed.
Results: After full adjustment, MetS was significantly associated with increased cancer prevalence (OR = 1.338, 95% CI: 1.074-1.666, p = 0.010). This association was more pronounced in males (OR = 2.383, p < 0.05) and adults aged 20-65 years (OR = 1.573, p < 0.05). Mediation analysis revealed that PhenoAgeAccel significantly accounted for 16.5% of the total effect of MetS on cancer (Average Causal Mediation Effect = 0.00352, p < 0.001). Gender stratification indicated a statistically significant mediating effect in males (proportion mediated = 10.9%, p = 0.002) but not in females (proportion mediated = 10.9%, p = 0.086). The direct effect of MetS remained significant (OR = 1.265, p = 0.050).
Conclusion: MetS is associated with elevated cancer risk, with PhenoAgeAccel serving as a significant mediating pathway, particularly among males. These findings identify younger males as a high-risk subgroup for targeted preventive strategies.
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